Part of the series Topics in Medicinal Chemistry pp 1-35


Structure-Based Discovery of GPCR Ligands from Crystal Structures and Homology Models

  • Anirudh RanganathanAffiliated withScience for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University
  • , David RodríguezAffiliated withScience for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University
  • , Jens CarlssonAffiliated withScience for Life Laboratory, Department of Cell and Molecular Biology, Biomedical Center, Uppsala University Email author 

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The G protein-coupled receptor (GPCR) superfamily constitutes the largest group of human membrane proteins and plays key roles in diverse cellular processes. Major advances in structural biology for GPCRs have provided invaluable insights into ligand recognition and signaling for these important drug targets. Access to high-resolution crystal structures also enables rational ligand design and in silico methods based on atomic-resolution models are likely to play an increasingly important role in future drug development. In this chapter, examples of ligand discovery efforts based on molecular docking screening against GPCR crystal structures will be presented first. Results from these studies suggest that crystal structures can not only guide discovery of ligands but also predict their selectivity and signaling properties. As experimental structures are not available for a large fraction of the superfamily, methods for atomic-resolution modeling of GPCR–ligand complexes could make important contributions to drug discovery. In the second part of the chapter, the state-of-the-art in this area is discussed in light of three community-wide assessments, which have challenged the modeling community to blindly predict GPCR structures. Finally, several recent examples of successful ligand discovery efforts utilizing atomic-resolution models for GPCRs of unknown structure are summarized.


Agonist Antagonist Comparative modeling Drug discovery Fragment-based lead discovery G protein-coupled receptor Homology modeling Molecular docking Structure-based drug design Virtual screening